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Anal duct carcinoma is an uncommon malignancy of the glands of the anal duct. This entity poses a diagnostic challenge, both clinically and histologically. This article describes histopathologic findings in a case of anal duct carcinoma, including the initial diagnosis on biopsy and subsequent cytology specimens. Additionally, differential diagnoses of this neoplasm are discussed. With a high index of suspicion, and attention to histological and immunohistochemical features, anal duct carcinoma can be accurately diagnosed both on biopsy and on cytology.
Assuntos
Neoplasias do Ânus/patologia , Ascite/patologia , Carcinoma Ductal/diagnóstico , Citodiagnóstico/métodos , Dor Abdominal/diagnóstico , Dor Abdominal/etiologia , Ascite/etiologia , Biópsia/métodos , Carcinoma Ductal/complicações , Carcinoma Ductal/metabolismo , Constipação Intestinal/diagnóstico , Constipação Intestinal/etiologia , Diagnóstico Diferencial , Feminino , Cuidados Paliativos na Terminalidade da Vida , Humanos , Queratinas/metabolismo , Pessoa de Meia-Idade , Paracentese/métodos , Neoplasias Peritoneais/diagnósticoRESUMO
Upregulation of TGFß and Cox2 in the tumor microenvironment results in blockade of T-cell penetration into the tumor. Without access to tumor antigens, the T-cell response will not benefit from administration of the immune checkpoint antibodies. We created an intravenous polypeptide nanoparticle that can deliver two siRNAs (silencing TGFß and Cox2). Systemic administration in mice, bearing a syngeneic orthotopic hepatocellular carcinoma (HCC), delivers the siRNAs to various cells in the liver, and significantly reduces the tumor. At 2 mg/kg (BIW) the nanoparticle demonstrated a single agent action and induced tumor growth inhibition to undetectable levels after five doses. Reducing the siRNAs to 1mg/kg BIW demonstrated greater inhibition in the presence of PD-L1 mAbs. After only three doses BIW, we could still recover a smaller tumor and, in tumor sections, showed an increase in penetration of CD4+ and CD8+ T-cells deeper into the remaining tumor that was not evident in animals treated with non-silencing siRNA. The combination of TGFß and Cox2 siRNA co-administered in a polypeptide nanoparticle can act as a novel therapeutic alone against HCC and may augment the activity of the immune checkpoint antibodies. Silencing TGFß and Cox2 converts an immune excluded (cold) tumor into a T-cell inflamed (hot) tumor.
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Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additional BGN variant-harboring family members (9 males and 27 females). The identified BGN variants were shown to lead to loss-of-function by cDNA and Western Blot analyses of skin fibroblasts or were strongly predicted to lead to loss-of-function based on the nature of the variant. No (likely) pathogenic missense variants without additional (predicted) splice effects were identified. Interestingly, a male proband with a deletion spanning the coding sequence of BGN and the 5' untranslated region of the downstream gene (ATP2B3) presented with a more severe skeletal phenotype. This may possibly be explained by expressional activation of the downstream ATPase ATP2B3 (normally repressed in skin fibroblasts) driven by the remnant BGN promotor. This study highlights that aneurysms and dissections in MRLS extend beyond the thoracic aorta, affecting the entire arterial tree, and cardiovascular symptoms may coincide with non-specific connective tissue features. Furthermore, the clinical presentation is more severe and penetrant in males compared to females. Extensive analysis at RNA, cDNA, and/or protein level is recommended to prove a loss-of-function effect before determining the pathogenicity of identified BGN missense and non-canonical splice variants. In conclusion, distinct mechanisms may underlie the wide phenotypic spectrum of MRLS patients carrying loss-of-function variants in BGN.
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ABSTRACT: A subanesthetic intravenous ketamine infusion is a safe and effective acute pain management modality for moderate to severely painful surgical procedures and may be useful in patients who are at increased risk for opioid-related adverse events. Despite its safety profile, intravenous ketamine is often restricted to the intensive care unit, which results in decreased patient access to this effective therapy. For clinicians who wish to implement an intravenous ketamine protocol in the medical-surgical setting, there are few resources available. In this brief report, we present our ketamine infusion protocol for acute pain and the clinical and financial outcomes 1 year after implementation. In our experience, ketamine infusions on the medical-surgical ward are safe and cost-effective when an established acute pain service protocol is followed. Nurse practitioners play an essential role in increasing patient access to intravenous ketamine infusions and leading change by collaborating with stakeholders to develop a protocol, training nurses and interdisciplinary team members, and providing ongoing support to nursing staff.
Assuntos
Dor Aguda , Ketamina , Humanos , Ketamina/uso terapêutico , Dor Aguda/tratamento farmacológico , Dor Aguda/induzido quimicamente , Analgésicos Opioides/uso terapêutico , Infusões Intravenosas , Manejo da Dor , Analgésicos/uso terapêuticoRESUMO
Appendiceal mucinous neoplasms are rare findings defined by an accumulation of mucus within the vermiform appendix, and can be caused by a variety of conditions. Appendiceal mucinous neoplasms are important to consider because they can develop into pseudomyxoma peritonei as a consequence of perforation. We report a case of a 55-year-old man who initially presented with increasing abdominal girth, constipation, anorexia, and unintentional weight loss. Computed tomography examination of the abdomen and pelvis demonstrated a huge thin-walled cystic mass causing significant displacement of the surrounding abdominal and pelvic structures. The mass was amenable to resection and removed without perforation. Gross pathologic examination demonstrated a 44.0 × 40.0 × 23.0 cm unilocular cystic mass with a section of attached bowel. Microscopic examination revealed high-grade appendiceal mucinous neoplasm arising in a background of low-grade appendiceal mucinous neoplasm. This case report provides an evidence to include appendiceal mucinous neoplasms in the differential diagnosis of large abdominal cystic masses.
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Aldehyde dehydrogenases (ALDHs) catalyze the conversion of various aliphatic and aromatic aldehydes into corresponding carboxylic acids. Traditionally considered as housekeeping enzymes, new biochemical roles are being identified for members of ALDH family. Recent work showed that AldA from the plant pathogen Pseudomonas syringae strain PtoDC3000 (PtoDC3000) functions as an indole-3-acetaldehyde dehydrogenase for the synthesis of indole-3-acetic acid (IAA). IAA produced by AldA allows the pathogen to suppress salicylic acid-mediated defenses in the model plant Arabidopsis thaliana. Here we present a biochemical and structural analysis of the AldA indole-3-acetaldehyde dehydrogenase from PtoDC3000. Site-directed mutants targeting the catalytic residues Cys302 and Glu267 resulted in a loss of enzymatic activity. The X-ray crystal structure of the catalytically inactive AldA C302A mutant in complex with IAA and NAD+ showed the cofactor adopting a conformation that differs from the previously reported structure of AldA. These structures suggest that NAD+ undergoes a conformational change during the AldA reaction mechanism similar to that reported for human ALDH. Site-directed mutagenesis of the IAA binding site indicates that changes in the active site surface reduces AldA activity; however, substitution of Phe169 with a tryptophan altered the substrate selectivity of the mutant to prefer octanal. The present study highlights the inherent biochemical versatility of members of the ALDH enzyme superfamily in P. syringae.
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Aldeído Oxirredutases/metabolismo , Proteínas de Bactérias/metabolismo , Indóis/metabolismo , Pseudomonas syringae/enzimologia , Aldeído Oxirredutases/química , Aldeído Oxirredutases/genética , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Cinética , Modelos Moleculares , Mutagênese Sítio-Dirigida , Mutação , Conformação Proteica , Pseudomonas syringae/genética , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Excessive skin scars due to elective operations or trauma represent a challenging clinical problem. Pathophysiology of hypertrophic scars entails a prolonged inflammatory and proliferative phase of wound healing. Over expression of TGF-ß1 and COX-2 play key regulatory roles of the aberrant fibrogenic responses and proinflammatory mediators. When we silenced TGF-ß1 and COX-2 expression simultaneously in primary human fibroblasts, a marked increase in the apoptotic cell population occurred in contrast to those only treated with either TGF-ß1 or COX-2 siRNA alone. Furthermore, using human hypertrophic scar and skin graft implant models in mice, we observed significant size reductions of the implanted tissues following intra-scar administration of TGF-ß1/COX-2 specific siRNA combination packaged with Histidine Lysine Polymer (HKP). Gene expression analyses of those treated tissues revealed silencing of the target gene along with down regulations of pro-fibrotic factors such as α-SMA, hydroxyproline acid, Collagen 1 and Collagen 3. Using TUNEL assay detection, we found that the human fibroblasts in the implanted tissues treated with the TGF-ß1/COX-2siRNAs combination exhibited significant apoptotic activity. Therefore we conclude that a synergistic effect of the TGF-ß1/COX-2siRNAs combination contributed to the size reductions of the hypertrophic scar implants, through activation of fibroblast apoptosis and re-balancing between scar tissue deposition and degradation.
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The expression of the Drosophila calmodulin (CAM) gene is surprisingly complex. The nervous system, which shows intense transcription in embryogenesis, contains no detectable transcripts at the end of larval life, but becomes transcriptionally active again at pupariation. The gut shows high levels of expression throughout the life cycle, except during pupal reorganization. In contrast, CAM expression in the thoracic muscles drops significantly on transition from pupal to adult life. In the testis, transcription is strongly up-regulated prior to meiosis. Growing cells show lower transcript levels than most differentiated tissues and in general, cells with intense exocytotic or endocytotic activity show the highest mRNA levels.